BackgroundPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The high risk of recurrence following surgical resection provides the rationale for adjuvant therapy. However, only a subset of patients benefit from adjuvant therapy. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of novel candidate biomarkers, including microRNAs, can predict clinical outcome in PDAC patients treated with adjuvant therapy.Methodology/Principal FindingsFormalin-fixed paraffin embedded specimens from a cohort of 82 resected Korean PDAC cases were analyzed for protein expression by immunohistochemistry and for microRNA expression using quantitative Real-Time PCR. Cox proportional hazards model analysis in the subgroup of patients treated with adjuvant therapy (N = 52) showed that lower than median miR-21 expression was associated with a significantly lower hazard ratio (HR) for death (HR = 0.316; 95%CI = 0.166–0.600; P = 0.0004) and recurrence (HR = 0.521; 95%CI = 0.280–0.967; P = 0.04). MiR-21 expression status emerged as the single most predictive biomarker for treatment outcome among all 27 biological and 9 clinicopathological factors evaluated. No significant association was detected in patients not treated with adjuvant therapy. In an independent validation cohort of 45 frozen PDAC tissues from Italian cases, all treated with adjuvant therapy, lower than median miR-21 expression was confirmed to be correlated with longer overall as well as disease-free survival. Furthermore, transfection with anti-miR-21 enhanced the chemosensitivity of PDAC cells.Conclusions SignificanceLow miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of PDAC cases, and anti-miR-21 increased anticancer drug activity in vitro. These data provide evidence that miR-21 may allow stratification for adjuvant therapy, and represents a new potential target for therapy in PDAC.

Protein kinase RNA-activated (PKR) induces immune response by sensing viral double-stranded RNAs (dsRNAs). However, growing evidence suggests that PKR can also be activated by endogenously expressed dsRNAs. Here, we capture these dsRNAs by formaldehyde-mediated crosslinking and immunoprecipitation sequencing and find that various noncoding RNAs interact with PKR. Surprisingly, the majority of the PKR-interacting RNA repertoire is occupied by mitochondrial RNAs (mtRNAs). MtRNAs can form intermolecular dsRNAs owing to bidirectional transcription of the mitochondrial genome and regulate PKR and eIF2α phosphorylation to control cell signaling and translation. Moreover, PKR activation by mtRNAs is counteracted by PKR phosphatases, disruption of which causes apoptosis from PKR overactivation even in uninfected cells. Our work unveils dynamic regulation of PKR even without infection and establishes PKR as a sensor for nuclear and mitochondrial signaling cues in regulating cellular metabolism.

Background & Aims-Intestinal metaplasia (IM) and spasmolytic polypeptide-expressing metaplasia (SPEM) are precursors to gastric carcinogenesis. We sought to identify molecular biomarkers of gastric metaplasias and gastric cancer by gene expression profiling of metaplastic lesions from patients.

By using specific CT criteria, ectopic pancreas can be differentiated from small GIST or leiomyoma with a high degree of accuracy.

Loss of epithelial proteins and/or the acquisition of mesenchymal proteins are associated with poorly differentiated histology, advanced stage and poor outcome in GC. The awareness and inhibition of EMT offer a promising target for prevention of metastatic progression and invasion.

AimsTo determine the extent of HER2 homogeneity/heterogeneity in primary versus metastatic gastric carcinoma (GC).Materials and resultsThe human epidermal growth factor receptor 2 (HER2) status in primary and metastatic lesions was evaluated by immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH). Four separate cohorts consisting of primary GC alone or primary GC paired with metastatic lesions were examined. In the FISH analysis of 325 primary GCs, eight cases (2.5%) showed amplification with a heterogeneous pattern, whereas 27 cases (8.3%) showed amplification with a homogeneous pattern, and in this cohort the discordant:concordant FISH ratio based on examination of three different areas in each primary lesion was 0.30:1. FISH testing using 250 paired primary and metastatic lesions revealed seven cases (2.8%) with discordant amplification. In metastatic disease positive conversion occurred in six cases (2.4%), whereas negative conversion happened in one case (0.4%). The discordant:concordant ratio of primary versus secondary lesions was 0.23:1. When the seven discordant cases were re-evaluated using whole sections of primary GCs, six showed a heterogeneous pattern of amplification.ConclusionsThese findings suggest that the discordant HER2 amplification observed in metastatic lesions is explained substantially by heterogeneity within primary tumours.

A variety of tumors, including primary malignant tumors, secondary malignant tumors, and benign tumors, can occur in the tracheobronchial tree. Primary malignant tumors commonly originate from the surface epithelium or the salivary glands, whereas most benign tumors arise from the mesenchymal tissue. At computed tomography (CT), primary malignant tumors manifest as a polypoid lesion, a focal sessile lesion, eccentric narrowing of the airway lumen, or circumferential wall thickening. At fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET), most squamous cell carcinomas show high uptake, whereas adenoid cystic carcinoma and mucoepidermoid carcinoma show variable uptake depending on the grade of differentiation. High-grade malignancies tend to show high and homogeneous uptake. Carcinoid tumors commonly show intense enhancement at contrast material-enhanced CT, which can be helpful in making the diagnosis, and usually have lower uptake at FDG PET than would be expected for a malignant tumor. Secondary malignant tumors occur as a result of either hematogenous metastasis or direct invasion by a malignancy from an adjacent structure. Their CT manifestations are similar to those of primary malignant tumors, with uptake at FDG PET depending primarily on the metabolic activity and degree of differentiation of the primary tumor. Among the benign tumors, hamartoma and lipoma can show characteristic CT findings such as "popcorn" calcification or internal fat. However, CT findings in most benign tumors are nonspecific. At FDG PET, benign tumors usually show little or no uptake and can be differentiated from malignant tumors. Knowledge of the characteristic CT and FDG PET findings of tracheobronchial tumors can aid in diagnosis and treatment planning.

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